This is the peer reviewed version of the following article: Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial. Br J Pharmacol. 2019. https://doi.org/10.1111/bph.14621, which has been published in final form at  https://doi.org/10.1111/bph.14621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis   work   was   supported   by   a   British   Heart   Foundation   Project   Grant (PG/11/88/28992)  and  the  National  Institutes  for  Health  Research,  Comprehensive Biomedical Research Centre award to UC

Baliga, RS

Chowdhury, K

Coghlan, GJ

Dore, CJ

Ghedia, D

Hobbs, AJ

MacAllister, RJ

Maclagan, K

Moyes, AJ

Ochiel, R

Quartly, HL

Schreiber, BE

Smit, A

Sofat, R

Sylvestre, Y

British Journal of Pharmacology

English

Jin H. K.

Llorens‐Cortes C.

Crossref

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodeling and right ventricular failure. In pre-clinical models, combination of a phosphodiesterase 5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cyclic GMP signaling, and reverses the structural and hemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. EXPERIMENTAL APPROACH: 21 PAH patients stable on PDE5i therapy were recruited. Acute hemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14 day safety and efficacy evaluation. The primary endpoint in both steps was circulating atrial natriuretic peptide (ANP) concentration (Δmax ), with secondary outcomes including pulmonary and systemic hemodynamics plus mechanistic biomarkers. KEY RESULTS: Acute administration of racecadotril (100mg) resulted in a 79% (95%CI, +6,+203) increase in the plasma ANP concentration and a 106% (+28,+229) increase in plasma cyclic GMP levels, with a concomitant 14% (-24,-3) fall in pulmonary vascular resistance. Racecadotril (100mg; tid) treatment for 14 days resulted in a 19% (-18,+72) rise in plasma ANP concentration. Neither acute (-16%,-28,+1) nor chronic (-4%, -21,+16) administration of racecadotril resulted in a significant drop in MABP or any serious adverse effects. CONCLUSIONS AND IMPLICATIONS: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger-scale prospective trial

Doré, CJ

Coghlan, JG

UCL Discovery

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial

Queen Mary Research Online

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/55912/Hobbs%20et%20al.%202019.%20Neprilysin%20inhibition.pdf?sequence=2&isAllowed=y

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial

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UCL Discovery

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